A biodegradable theranostic sonosensitizer for afterglow-guided sonodynamic therapy

Optical imaging is crucial in biology and medicine, yet fluorescence imaging suffers from poor tissue penetration, low signal-to-background ratio (SBR), and limited sensitivity/specificity. Ultrasound (US) imaging, being a non-invasive and widely used modality for anatomical and functional visualization, offers a promising source of activation for luminescence. However, designing degradable sonosensitizers for US-triggered afterglow emission remains challenging, necessitating efficient US-luminescence strategies. Here, we address this by developing a triphenylphosphonium cation (TPP⁺)-modified protoporphyrin IX derivative (PpIX-M). The TPP⁺ modification suppresses π-π stacking of the porphyrin plane, enhancing fluorescence quantum yield. Furthermore, TPP⁺ acts as an electron acceptor, promoting charge separation, prolonging phosphorescence lifetime, and thereby boosting reactive oxygen species (ROS) generation. Notably, PpIX-M achieves US-triggered Type I and II ROS-driven afterglow luminescence, with an afterglow lifetime reaching 20 min and an exceptional in vivo afterglow imaging SBR of 48.6. Under afterglow imaging guidance, effective sonodynamic therapy (SDT) was realized, inducing tumor cell ferroptosis and apoptosis. This study demonstrates the feasibility of TPP⁺-regulated fluorescence and ROS enhancement for ultrasound-induced luminescence imaging in vivo, offering valuable insights for the development of next-generation ultrasound-activated afterglow probes and advancing the field of ultrasound-based luminescence imaging. STATEMENT OF SIGNIFICANCE: This work develops a sonosensitizer, PpIX-M, that integrates imaging and therapeutic functions. Its molecular design enhances key properties, allowing it to generate reactive oxygen species and produce a 20-minute afterglow under ultrasound. This enables high-contrast imaging while simultaneously delivering a sonodynamic therapy that triggers ferroptosis and apoptosis in cancer cells. The built-in self-degrading property of the agent reduces potential long-term toxicity. This combined approach provides a practical strategy for real-time treatment monitoring and precise tumor ablation.